补充维生素D_3协同第二代抗组胺药物治疗慢性自发性荨麻疹的临床疗效观察和作用机制研究
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摘要
目的:评价补充维生素D_3(VD3)协同第二代抗组胺药物对控制慢性自发性荨麻疹(CSU)临床症状的疗效。方法:①90例CSU患者,21例慢性可诱导性荨麻疹(CIndUI)和55例健康自愿者选自武汉大学人民医院皮肤科门诊(2017年10月至2018年10月);②受试者进行血清25羟维生素D_3[25-(OH)D_3],血浆D-二聚体(D-dimer)、纤维蛋白降解产物(FDP),血沉(ESR)等实验室检查,并给予荨麻疹活动度评分(UAS7);③分离和体外培养正常人与CSU患者各15例外周血单个核细胞(PBMC),经1 nM和10 nM 1α,25-(OH)_2D_3处理后用实时荧光定量PCR技术检测白介素-6(IL-6)和维生素D受体(VDR)mRNA的表达水平;④VD3严重缺乏(血清浓度<10 ng/mL)的患者补充大剂量(2400 IU/d)VD3,缺乏者(10～20 ng/mL)给予补充小剂量(800 IU/d)VD3,设未补充患者作对照,于6周和12周时再行UAS7评分。结果:与健康对照组相比,CSU患者血清25-(OH)D_3水平明显减少,D-dimer、FDP及ESR水平明显增加,且与UAS7评分呈正相关;qPCR结果显示15例CSU患者PBMC IL-6和VDR mRNA表达水平较正常人明显增加;经1α,25-(OH)_2D_3处理后,IL-6 mRNA表达减少,VDR mRNA表达增加(P<0.05);与未补充组比较,VD3严重缺乏组给予补充大剂量VD3 12周,UAS7评分明显下降(P<0.0001)。结论:补充VD3有助于协同控制CSU的临床症状,可能与其抑制了荨麻疹亚临床炎症有关。
Objective: To evaluate the beneficial effect of the therapeutic regimen supplemented with vitamin D_3(VD3) on chronic spontaneous urticaria(CSU). Methods: From Oct.2017 to Oct, 2018, 90 patients with CSU, 21 patients with chronic inducible urticaria(CIndU) and 55 healthy subjects were recruited from Department of Dermatology, Renmin Hospital of Wuhan University. Routine laboratory tests including the levels of serum 25-(OH)D_3, plasma D-dimer, fibrin degradation products(FDP) and erythrocyte sedimentation rate(ESR) were carried out, meanwhile, the urticaria activity score 7(UAS7) was recorded for each patients at baseline and each follow-up. Peripheral blood mononuclear cells(PBMCs) were collected and purified from 15 CSU patients and 15 healthy subjects. PBMCs were cultured with fresh complete RPMI 1640 medium containing 10 μg/mL phytohaemagglutinin(PHA) and treated with 1α,25-(OH)_2D_3 at varying concentrations. After treatment, the cells were harvested and used for measuring the mRNA levels of IL-6 and vitamin D receptor(VDR) using real-time fluorescent quantitative PCR(qPCR). CSU patients with severe VD3 deficiency(less than 10 ng/mL of serum 25-(OH)D_3) were treated with 2400 IU VD3 per day, the patients with VD3 deficiency(10-20 ng/mL of serum 25-(OH)D_3) were treated with 800 IU VD3 per day. The patients without VD3 treatment served as negative control. All patients were assessed by UAS7 at 6 and 12 weeks post-treatment. Results: The levels of serum 25-(OH)D_3 were significantly lower in the patients with CSU as compared with the healthy controls. The levels of D-dimer, FDP, ESR were significantly higher than the healthy controls. The increases in the levels of D-dimer, FDP, and ESR were also positively correlated with the UAS7 assessment. qPCR results showed that the transcript levels of IL-6 and VDR were elevated in PBMC derived from 15 CSU patients in comparison with the healthy controls.The decreased IL-6 levels and enhanced VDR levels were observed in the PBMCs exposed to 1α,25-(OH)_2D_3,all P<0.05. Moreover, we also found that UAS7 score was much lower in patients with severe VD3 deficiency and treated with VD3 than that in untreated controls at 12 weeks post-treatment, P<0.0001.Conclusion: VD3 supplement may be beneficial for resolving the clinical symptoms of CSU, possibly through its inhibition of subclinical inflammation in urticaria.
Objective: To evaluate the beneficial effect of the therapeutic regimen supplemented with vitamin D_3(VD3) on chronic spontaneous urticaria(CSU). Methods: From Oct.2017 to Oct, 2018, 90 patients with CSU, 21 patients with chronic inducible urticaria(CIndU) and 55 healthy subjects were recruited from Department of Dermatology, Renmin Hospital of Wuhan University. Routine laboratory tests including the levels of serum 25-(OH)D_3, plasma D-dimer, fibrin degradation products(FDP) and erythrocyte sedimentation rate(ESR) were carried out, meanwhile, the urticaria activity score 7(UAS7) was recorded for each patients at baseline and each follow-up. Peripheral blood mononuclear cells(PBMCs) were collected and purified from 15 CSU patients and 15 healthy subjects. PBMCs were cultured with fresh complete RPMI 1640 medium containing 10 μg/mL phytohaemagglutinin(PHA) and treated with 1α,25-(OH)_2D_3 at varying concentrations. After treatment, the cells were harvested and used for measuring the mRNA levels of IL-6 and vitamin D receptor(VDR) using real-time fluorescent quantitative PCR(qPCR). CSU patients with severe VD3 deficiency(less than 10 ng/mL of serum 25-(OH)D_3) were treated with 2400 IU VD3 per day, the patients with VD3 deficiency(10-20 ng/mL of serum 25-(OH)D_3) were treated with 800 IU VD3 per day. The patients without VD3 treatment served as negative control. All patients were assessed by UAS7 at 6 and 12 weeks post-treatment. Results: The levels of serum 25-(OH)D_3 were significantly lower in the patients with CSU as compared with the healthy controls. The levels of D-dimer, FDP, ESR were significantly higher than the healthy controls. The increases in the levels of D-dimer, FDP, and ESR were also positively correlated with the UAS7 assessment. qPCR results showed that the transcript levels of IL-6 and VDR were elevated in PBMC derived from 15 CSU patients in comparison with the healthy controls.The decreased IL-6 levels and enhanced VDR levels were observed in the PBMCs exposed to 1α,25-(OH)_2D_3,all P<0.05. Moreover, we also found that UAS7 score was much lower in patients with severe VD3 deficiency and treated with VD3 than that in untreated controls at 12 weeks post-treatment, P<0.0001.Conclusion: VD3 supplement may be beneficial for resolving the clinical symptoms of CSU, possibly through its inhibition of subclinical inflammation in urticaria.
引文
[1] Saini SS. Chronic spontaneous urticaria[J]. Immunol Allergy Clin North Am,2014,34(1):33-52.
[2] Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update[J]. J Allergy Clin Immunol,2014,133(5):1270-1277.
[3] Rasool R, Masoodi KZ, Shera IA, et al. Chronic urticaria merits serum vitamin D evaluation and supplementation; a randomized case control study[J]. World Allergy Organ J,2015,8(1):1-10.
[4] Rorie A, Goldner WS, Lyden E, et al. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study[J]. Ann Allergy Asthma Immunol,2014,112(4):376-382.
[5] Grzanka A, Machura E, Mazur B, et al. Relationship between vitamin D status and the inflammatory state in patients with chronic spontaneous urticaria[J]. J Inflamm (Lond),2014,11(1):2.
[6] Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[J]. Allergy,2018,73(7):1393-1414.
[7] Rausch-Fan X, Leutmezer F, Willheim M, et al. Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific Th cell clones by 1 alpha,25-dihydroxyvitamin D-3[J]. Int Arch Allergy Immunol,2002,128(1):33-41.
[8] 何晓蕾,雷铁池,刘小明,等.自体血清皮肤试验对诊断慢性荨麻疹的临床意义[J].中华皮肤科杂志,2012,45(1):5-8.
[9] Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health[J]. Am J Clin Nutr,2008,88(2):491S-499S.
[10] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences[J]. Am J Clin Nutr,2008,87(4):1080S-1086S.
[11] Pereira-Santos M, Costa PRF, Assis AMO, et al. Obesity and vitamin D deficiency: a systematic review and meta-analysis[J]. Obes Rev,2015,16(4):341-349.
[12] Woo YR, Jung KE, Koo DW, et al. Vitamin D as a marker for disease severity in chronic urticaria and its possible role in pathogenesis[J]. Ann Dermatol,2015,27(4):423.
[13] Kolkhir P, Altrichter S, Hawro T, et al. C-reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria[J]. Allergy,2018,73(4):940-948.
[14] Zhang Y, Leung DYM, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1[J]. J Immunol,2012,188(5):2127-2135.
[15] Liu ZQ, Li XX, Qiu SQ, et al. Vitamin D contributes to mast cell stabilization[J]. Allergy,2017,72(8):1184-1192.
[16] Thompson PD, Jurutka PW, Kerr Whitfield G, et al. Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements[J]. Biochem Biophys Res Commun,2002,299(5):730-738.
[2] Bernstein JA, Lang DM, Khan DA, et al. The diagnosis and management of acute and chronic urticaria: 2014 update[J]. J Allergy Clin Immunol,2014,133(5):1270-1277.
[3] Rasool R, Masoodi KZ, Shera IA, et al. Chronic urticaria merits serum vitamin D evaluation and supplementation; a randomized case control study[J]. World Allergy Organ J,2015,8(1):1-10.
[4] Rorie A, Goldner WS, Lyden E, et al. Beneficial role for supplemental vitamin D3 treatment in chronic urticaria: a randomized study[J]. Ann Allergy Asthma Immunol,2014,112(4):376-382.
[5] Grzanka A, Machura E, Mazur B, et al. Relationship between vitamin D status and the inflammatory state in patients with chronic spontaneous urticaria[J]. J Inflamm (Lond),2014,11(1):2.
[6] Zuberbier T, Aberer W, Asero R, et al. The EAACI/GA2LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria[J]. Allergy,2018,73(7):1393-1414.
[7] Rausch-Fan X, Leutmezer F, Willheim M, et al. Regulation of cytokine production in human peripheral blood mononuclear cells and allergen-specific Th cell clones by 1 alpha,25-dihydroxyvitamin D-3[J]. Int Arch Allergy Immunol,2002,128(1):33-41.
[8] 何晓蕾,雷铁池,刘小明,等.自体血清皮肤试验对诊断慢性荨麻疹的临床意义[J].中华皮肤科杂志,2012,45(1):5-8.
[9] Norman AW. From vitamin D to hormone D: fundamentals of the vitamin D endocrine system essential for good health[J]. Am J Clin Nutr,2008,88(2):491S-499S.
[10] Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences[J]. Am J Clin Nutr,2008,87(4):1080S-1086S.
[11] Pereira-Santos M, Costa PRF, Assis AMO, et al. Obesity and vitamin D deficiency: a systematic review and meta-analysis[J]. Obes Rev,2015,16(4):341-349.
[12] Woo YR, Jung KE, Koo DW, et al. Vitamin D as a marker for disease severity in chronic urticaria and its possible role in pathogenesis[J]. Ann Dermatol,2015,27(4):423.
[13] Kolkhir P, Altrichter S, Hawro T, et al. C-reactive protein is linked to disease activity, impact, and response to treatment in patients with chronic spontaneous urticaria[J]. Allergy,2018,73(4):940-948.
[14] Zhang Y, Leung DYM, Richers BN, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1[J]. J Immunol,2012,188(5):2127-2135.
[15] Liu ZQ, Li XX, Qiu SQ, et al. Vitamin D contributes to mast cell stabilization[J]. Allergy,2017,72(8):1184-1192.
[16] Thompson PD, Jurutka PW, Kerr Whitfield G, et al. Liganded VDR induces CYP3A4 in small intestinal and colon cancer cells via DR3 and ER6 vitamin D responsive elements[J]. Biochem Biophys Res Commun,2002,299(5):730-738.